Cabergoline is a dopamine agonist that has been used clinically to treat prolactinomas, Parkinson's disease, and Cushing's disease and has been reported to have positive effects in patients suffering from depression (see Verhelst, J., et al. J Clin Endocrinol Metab 1999, 84, 2518; Odin, P., et al. Acta Neurologica Scandinavica 2006, 113, 18; Petrossians, P., et al. Neuroendocrinology 2010, 92, 116; Vilar, L., et al. Pituitary 2010, 13, 123; Castillo, V. A., et al. Research in Veterinary Science 2008, 85, 26; Takahashi, H., et al. Clin. Neuropharmacol. 2003, 26, 230; and Chiba, S., et al. Psychopharmacology 2010, 211, 291. Cabergoline is also used clinically to treat patients suffering from male sexual dysfunction, especially those with elevated prolactin levels (see Nickel, M., et al. Int J Impot Res 2006, 19, 104; De Rosa, M., et al. Eur J Endocrinol 1998, 138, 286; and Safarinejad, M. R. Int J Impot Res 2006, 18, 550). An elevated level of prolactin is a known risk factor for sexual dysfunction and cabergoline lowers the level of this hormone by binding to D2 receptors in the pituitary and inhibiting prolactin synthesis (see Zhang, W., et al. Horm Metab Res 2010, 42, 557). Cabergoline is also an agonist at the D4 and 5-HT1A receptors, both of which are believed to play important roles in regulating sexual function both in males and females (see Millan, M. J., et al. Journal of Pharmacology and Experimental Therapeutics 2002, 303, 791; Kvernmo, T., et al., Clinical Therapeutics 2006, 28, 1065; Newman-Tancredi, A., et al. Journal of Pharmacology and Experimental Therapeutics 2002, 303, 815; Brioni, J. D., et al. Proceedings of the National Academy of Sciences of the United States of America 2004, 101, 6758; Guptarak, J., et al. Hormones and Behavior 2010, 58, 290; Ben Zion, I. Z, et al. Mol Psychiatry 2006, 11, 782; and Sukoff Rizzo, S. J., et al. The International Journal of Neuropsychopharmacology 2009, 12, 1045).
Unfortunately, cabergoline is also a potent agonist of the 5-HT2B receptor (with a reported Ki of 1.2 nM) and, like other 5-HT2B agonists such as nor-dexfenfluramine, is known to cause cardiac-valve regurgitation (CVR) in patients. This potentially fatal complication has greatly limited the clinical use of cabergoline, especially in indications requiring high doses of the drug (see Newman-Tancredi, A., et al. Journal of Pharmacology and Experimental Therapeutics 2002, 303, 815; Rothman, R. B., et al. Circulation 2000, 102, 2836; Roth, B. L. N Engl J Med 2007, 356, 6; and Schade, R, et al. New England Journal of Medicine 2007, 356, 29.
In spite of the above reports, there is currently a need for therapeutic agents that have the useful therapeutic properties of cabergoline, but that lack the unwanted effects associated with agonism of the 5-HT2B receptor.